The present invention relates to an apheresis machine and a method for producing blood products using the same. More specifically, the present invention relates to customizing a collection process of whole blood during a cycle for improving cycle efficiency in an apheresis machine and production efficiency of blood products, and for lowering the level of contamination by white blood cells.
Apheresis is a procedure in which whole blood is separated into its various blood components, i.e., a higher density component such as red blood cells, at least one intermediate density component such as platelets and white blood cells, including lymphocytes and granulocytes, and a lower density component such as plasma, for collecting a desired blood component or components. Various methods are available for conducting apheresis, among which an intermittent blood flow method, according to which whole blood is intermittently processed with the use of centrifugation, is prevailing.
Among various blood component products obtainable through apheresis, the demand for concentrated platelet products is rapidly growing. This is particularly because, with the improvement in cancer therapy, there is a need to administrate more and more platelets to patients with lowered hemopoietic function. Platelets are fragments of a large cell located in the marrow called a megakaryocyte and primarily contribute to hemostasis by performing aggregation function, although they also have a role in tissue healing. Normal platelet counts are 150,000-400,000/mm3 in the adult. Platelet counts under 20,000/mm3 can cause various troubles such as spontaneous bleeding.
Platelets have a short half-life of 4-6 days and the number of donors is limited. Therefore, in producing concentrated platelet products, it is important to harvest platelets from the whole blood supplied by a donor at a maximum yield and in a required amount. Further, it is known that the contamination of concentrated platelet product by white blood cells can lead to serious medial complications, such as GVH reactions and, therefore, it is also very important to keep the level of contamination by white blood cells as low as possible, while efficiently collecting platelets. To this end, various excellent techniques have been developed. For example, according to the so-called xe2x80x9csurgexe2x80x9d technology developed by the assignee of the present application, after whole blood is collected and concentrically separated within a centrifuge into higher density, intermediate density and lower density components (so-called xe2x80x9cdrawxe2x80x9d step) and plasma is harvested, the plasma is supplied through the centrifuge at a surge flow rate, that is, a flow rate that increases with time. By performing the surge, platelets can be preferentially displaced from the intermediate density components, which exist as a buffy coat mainly comprising a mixture of platelets and white blood cells, and concentrated platelet products can thereby be produced at an increased yield. Further, in Japanese Patent No. 2,776,988 (PCT/US94/01107) also owned by the assignee of the present application, a success in the improvement of separation between platelets and white blood cells was achieved by recirculating plasma at a constant rate through the centrifuge for a short period of time (so-called xe2x80x9cdwellxe2x80x9d step) so as to arrange platelets and white blood cells, which have close specific gravities, before displacing platelets from the centrifuge using the surge technology. In the common intermittent blood flow method, after harvesting a desired component or components, the residual blood components mostly comprising red blood cells are returned to the donor (so-called xe2x80x9creturnxe2x80x9d step).
Usually, about 500 ml of whole blood is processed during one cycle which comprises the above-mentioned successive steps. This amount is based on 15% or less of the total amount of blood in humans and, if more than this amount is taken out of the body at once, the donor may suffer from blood pressure lowering or dizziness. This also means that there is a limit in the amount of a concentrated platelet product that can be harvested from one cycle and, in normal apheresis, a cycle which may require about 15 minutes is successively conducted for three to five times. The number of cycles is determined based on information previously obtained on the donor and his or her whole blood, for example, the donor""s sex, height and weight, the number of cells in the whole blood, hematocrit value and the like. Typically, the amount of a concentrated platelet product that can be harvested per cycle is determined based on this information, and the number of cycles is selected so as to satisfy a target number of platelets.
As is well-known, concentrated platelet products are administered or traded on the basis of the number of platelets contained therein, i.e., number of units. For example, according to the Pharmaceutical Affairs Law in Japan, the presence of 1xc3x971011 platelets in a bag is prescribed as 5 units, and the products are used in a discrete number of units, 5, 10, 15 or 20. Accordingly, for example, 11 units and 14 units are both regarded as only 10 units. However, in actual apheresis, an attempt to produce a 10-unit concentrated platelet product does not always result in the desired product. Specifically, assume, for example, that it has been determined from previously obtained information that a 4-unit concentrated platelet product may be produced from one cycle. In this case, while 2.5 cycles should be sufficient for producing a 10-unit concentrated platelet product, it is actually necessary to perform 3 cycles because number of cycles must be an integer, resulting in 12 units of platelets contained in a bag. This presents a problem in terms of efficient production of concentrated platelet products. Further, even if 3.5 units is to be produced from one cycle, in which case 3 cycles theoretically result in 10.5 units, i.e., a 10-unit concentrated platelet product, the operator tends to select 4 cycles for the sake of certainty because the number of actually harvestable platelets may vary. This causes a problem that the number of platelets actually present in a bag tends to exceed the number of units indicated on the bag. In such a case, excessive platelets are collected from a donor, and the time needed to collect blood becomes unduly long. This also presents a problem in securing the safety of a donor. It is to solve these problems that the present invention is directed.
In accordance with the present invention, the volume of whole blood to be processed in a centrifuge during a xe2x80x9cdrawxe2x80x9d step is variably controlled in response to at least one characteristic associated with the whole blood collected or to be collected from a donor. Specifically, in accordance with the present invention, a process volume of whole blood is increased or decreased so as to be customized with respect to each individual apheresis, so that the volume of an intermediate density blood component to be actuary harvested, in particular the number of platelets, becomes substantially equal to a desired number of units. The characteristics of whole blood are typically the number of platelets and hematocrit value, but the total amount of whole blood, which can be calculated based on the sex, height, weight and the like of a donor, as well as other characteristics, can also be considered. In addition, in case the separation of a desired number of white blood cells should be sought, the present invention is equally applicable.
In a draw step, using a first pump such as a peristaltic pump, whole blood is collected into a centrifuge from a donor directly, or after once pooled in a container such as a bag. The centrifuge may, for example, be a standard Latham bowl as described in US Pat. No. 3,145,713 (the contents of which is hereby incorporated by reference), has an inlet port and an outlet port and separates the collected whole blood into each component. In a draw step, it has been conventional to recirculate separated plasma by a second pump, which may also be a peristaltic pump, into the centrifuge at a constant flow rate such as 20 to 30 ml/min. for diluting the whole blood to facilitate its collection. Plasma is collected, for example, in a first container or bag which is connected to the centrifuge such that it can receive plasma from the outlet port and return it to the inlet port. In the second and the following cycles, the plasma collected in the previous cycle or cycles may be used.
According to one aspect of the present invention, a process volume of whole blood is decreased or increased by variably controlling the above second pump so as to increase or decrease the flow rate of plasma, i.e., the recirculation flow rate. The collection of whole blood in the draw step is continued until it is detected that the volume of a blood component separated in the centrifuge, typically the volume of a layer of red blood cells, has reached a predetermined amount. As mentioned above, the conventional amount of whole blood that may be collected from one cycle until this detection is, for example, about 500 ml. It is added that the detection can be made, for example, with an optical sensor which monitors the radius of the region occupied by the separated blood component in the centrifuge and detects when the radius has reached a particular value.
When, for example, the recirculation flow rate is increased here, the filling density of red blood cells within the layer of red blood cells is lowered at the time the radius has reached the above particular value, i.e., at the time the same volume has been occupied. This means that the number of platelets that can be harvested from one cycle decreases. Therefore, for example, when it has been previously determined from the hematocrit value, the number of platelets and the like of the whole blood of a donor that 3 units of platelets can be harvested from normal one cycle, the recirculation flow rate can be increased for decreasing the process volume of whole blood in the centrifuge so as to decrease the harvestable platelets units to about 2.7. While the same 4 total cycles are needed in either case to produce a 10-unit concentrated platelets product, when the recirculation flow rate is increased, the amount of excessively harvested platelets is decreased and the concentrated platelets product is produced more efficiently. On the other hand, in the above example, it is also possible to decrease the recirculation flow rate so that red blood cells are more densely filled in the layer of red blood cells and the number of platelets units to be harvested from one cycle becomes, for example, 3.5. According to this example, the desired 10-unit concentrated platelets product can be produced through three cycles, and this is preferred for efficient production and for not restricting the donor unduly longer.
In accordance with the present invention, it has been found that a decrease in the process volume of whole blood per cycle through increase in the recirculation flow rate also decreases, at the same time, the contamination by white blood cells in a resultant concentrated platelets product. Therefore, from this point of view, it is preferable to control the second pump so as to increase the recirculation flow rate for decreasing the process volume of whole blood per cycle, even if the total number of cycles remains the same, rather than decreasing the number of cycles by increasing the process volume of whole blood. In such a case, control means in accordance with the present invention can be adapted to perform an automatic operation in which a total number of cycles that exceeds a desired number of product units is determined based on the number of platelets that can be harvested per cycle and the process volume of whole blood per cycle is decreased so that the total amount of platelets to be harvested from the total cycles will not excessively go beyond the desired number of product units. Such decrease in the process volume of whole blood per cycle through an increase in the recirculation flow rate is also advantageous, especially if the donor is physically relatively petit and the total amount of available blood is limited, because the amount of extracorporeal blood circulation will be decreased and thus the danger of causing anemia or dizziness can be minimized.
On the other hand, however, it should be noted that decrease in the recirculation flow rate does not necessarily mean that contamination by white blood cells will increase. Such is a matter that may also be affected by the hematocrit value of donated whole blood and the like. Therefore, it is also possible to configure the above-mentioned automatic operation so that the process volume of whole blood per-cycle will be automatically decreased or increased according to hematocrit values or any other suitable threshold values.
Further, for example in Multi or CCS, which are the names of products marketed by Haemonetics Corporation, the assignee of the present application, the total amount of plasma flowing through the centrifuge, i.e., the so-called critical flow, is controlled to promote a separation between platelets and white blood cells. It is also possible to increase or decrease the recirculation flow rate by the second pump such that the critical flow is increased or decreased, and the process volume of whole blood is variably controlled thereby. As is known, the critical flow can be maintained constant by controlling the recirculation flow rate of plasma with the second pump, and the critical flow is advantageous in that whole blood is diluted, fluctuations in the flow rate of whole blood being collected from a donor is compensated for and the flow through the centrifuge, or bowl is stabilized to prevent the separation from being disturbed. In fact, depending on the condition of a donor, the volume of whole blood supplied sometimes drops by 20 to 30 ml during the draw step, even to zero under certain circumstances. According to the critical flow technology, however, the second pump operates to increase the recirculation flow rate so as to compensate for the drop, thereby maintaining the critical flow at a constant level. Then, according to the present invention, the second pump can be further controlled to increase or decrease the flow rate of the critical flow itself so as to increase or decrease the process volume of whole blood.
According to another aspect of the present invention, the same effect as that of variably controlling the second pump can also be obtained by variably controlling the number of rotations of the centrifuge. Namely, when the number of rotations of the centrifuge is decreased, red blood cells are filled more coarsely in the layer of red blood cells and the process volume of whole blood per cycle is decreased accordingly. On the other hand, when the number of rotations of the centrifuge is increased, red blood cells are filled more densely in the layer of red blood cells and the process volume of whole blood per cycle is increased. In this case, it is also preferable to perform control so that the number of rotations of the centrifuge is decreased for reducing the process volume of whole blood per cycle, when it is desired to decrease the contamination by white blood cells in concentrated platelets products. To decrease the number of cycles for reducing the burden of donors, it is preferable to control the centrifuge so that the number of rotations is increased.
The aforementioned variable control of the second pump and variable control of the centrifuge can be carried out independently. Alternatively, they can be coordinated with each other so as to optimize the process volume per cycle. Therefore, according to the present invention, in response to previously available at least one characteristic associated with whole blood, such as a hematocrit value, the number of platelets, total blood amount and the like, an appropriate number of cycles can be set by taking variations into account, thereby enabling efficient production of concentrated platelets products without excessive collection. Alternatively, it is also possible to select in advance a desired number of cycles, and to conveniently set the number of units of a concentrated platelets product to be produced on this basis. The means for implementing such control can be realized by the use of a micro computer, which may be appropriately pre-programmed or configured to be loaded with an appropriate program according to situations. The above-mentioned automatic operation can be most suitably implemented in such cases.
It is desirable to conduct the dwell step after the draw step. This step is described in detail in the aforementioned Japanese Patent No. 2,776,988 (PCT/US94/01107), the contents of which patent is hereby incorporated by reference. In the dwell step, after the line for collecting whole blood to the centrifuge is closed, the lower density component, i.e., plasma, is circulated into the centrifuge for a short period of time at a substantially constant flow rate which is greater than the flow rate for collecting the whole blood. The buffy coat is thereby diluted in the centrifuge by the plasma and the region it occupies in the centrifuge is widened, resulting in an improved separation of the intermediate density components in the buffy coat, i.e., platelets and white blood cells. Namely, the widened buffy coat allows the heavier white blood cells to sediment more completely than the lighter platelets to the outer side of the buffy coat, thereby improving the separation between the white blood cells and the platelets. The improved separation between white blood cells and platelets reduces the degree of contamination by white blood cells in eventually collected platelets. The operation of the second pump can begin in response to a detection, for example by the aforementioned optical sensor or the like, that the radius of the area occupied by the intermediate density components has reached a particular value.
The surge step is carried out following the dwell step. That is, the second pump can be further operated to supply plasma to the centrifuge at a surge flow rate so as to displace the intermediate density components from the centrifuge. The surge flow rate is a flow rate which increases over a predetermined period of time. Platelets first, and then white blood cells under further increased flow rate, are successively displaced from the centrifuge. Blood components displaced from the centrifuge are monitored by an optical line sensor to determine in accordance with the optical density of the components that a particular component has been displaced. An uninterrupted length of passage or tube is in fluid communication with the outlet port of the centrifuge and extends from the outlet port beyond the optical line sensor. The displaced blood components are collected in second and third containers or bags, respectively, which are in selective fluid communication with the outlet port of the centrifuge through the uninterrupted passage. The uninterrupted passage prevents foam associated with the component displaced from the centrifuge from mixing with the component more completely, thereby preventing the optical line sensor from making false optical readings.
When the processed whole blood is directly withdrawn from the donor, the return step follows the surge step, in which the remaining blood components in the centrifuge, for example, red blood cells and white blood cells, are returned to the donor. In this case, the efficiency of returning blood can be increased by diluting the blood components with the second pump as described in Japanese Patent No 2,575,769. The cycle can then be repeated a desired number of times.